3-ethylene glycol ketal of 11alpha-lower alkyl 11beta-hydroxy-21-acyloxy-5, 17(20)-pregnadiene-3-one



2,880,204 7 3-ETHYLENE GIQYCOL KETAL or Ila-LOWER ALKYL 1IB-HYDROXY-Zl-ACYLOXY-S,17(20)- PREGNADIENE-d-ONE I Gunther S. Fonlren and John A. Hogg, Kalamazoo Township, Kalamazoo County, and Barney J. Magerlein, Kalamazoo, Mich., asslgnors to The Upjohn Company, I Kalamazoo, Mich., a corporation of Michigan No Drawing. Application May 23, 1955 Serial No. 510,516

5 Claims. (Cl. zen-239.55

.This invention relates to 1 1e-lower-alkyl-hydrocortisone and 21-esters thereof, intermediates in the production thereof, and ma process for their production.

It is an object ofthe present invention to provide 11ozlower-alkyl-hydrocortisone; especially lla-methyl-hydrocortisone and2,1 -'esters thereof; Another object is the provision of novel intermediates in the production thereof. A further object isthe provision of a process forthe production thereofu Other objects will be apparent to those skilled in the to whichthis invention pertains.

Ihe-l la-lower-alkyl hydrocortisone and 21-esters thereof, especially 1la -methybhydrocortisone and its 21-acetate, have anti-inflarnrr'iatory activity and are useful in the treatment of rheumatoid arthritis and other inflammatory conditions of the skin, eyes and ears of humans and valuable domestic'animals which are due to a variety of bacterial and fungal infections, contact dermatitis and other allergenic reactions.

The novel 1lit-lower-alkyl-hydrocortisones and intermediates in theproduction thereof may be represented by the following formulae:

ice

a V11 wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, R is a ketone protecting group, i.e.-, a cyclic ketal or an enol ether, R is a hydrocarbon radical containing from one to twenty carbon atoms, and R" is hydrogen or Ac as defined above. In Formulae III and IV, when R is an enolfether group, an additional double bond. in the 3(4) position is present in the molecule. The term lower-alkyl, when used herein, means alkyl containing from one to eight carbon atoms, inclusive.

The starting 21 acyloxy 4,17(20)'-pregnadiene-3,1l dione (I) can be prepared as disclosed in the copending application of Hogg, Beal and Lincoln, S.N. 345,675, filed March 30, 1953, i.e.,' treatment of l-l-ketoprogesterone with about a molar equivalent of sodium methoxide and an excess of diethyl oxalate in dry benzene and then brominating the thus-producedsoclium enolateof 11-keto-21-ethoxyoxalylprogesterone with two-molar equivalents of bromine in methanol containingpotassium acetate. Reacting the dibrominated product with more than twomolar equivalents of sodium methoxide in the same solvent'is productive of methyl 3,11-diketo-4,l7(20)- Refluxing this compound in [cis]-pregnadiene-2l-oate. methanol containing sodium methoxide converts it to the trans isomer. cis or trans isomer of methyl 3,11-diketo-4,17(20)-pregnadiene-21-oate with ethylene glycol in the usual manner, followed by the reduction of the ketalized compound with lithium aluminum hydride in ether and then hydrolysisv Ketalizing the 3-keto group of eithenthe cis or trans isomer of 1lfl-hydroxy-Z1-acyloxy-4,17(20)- pregnadiene-3-one. Oxidation of the ll-hydroxy group of these compounds with N-bromoacetamide in pyridine for eighteen hours or chromic acid in acetic acid and water is productive of the corresponding cis or trans isomer of 21 acyloxy 4,l7(20)-pregnadiene-3,11-dione (I).

In the reactions described hereinbelow, the preferred compounds I-VIII have the l7(20)-cis configuration. The cis isomers of VII can be converted in higher yield to VIII than the corresponding trans isomers.

In carrying out the ketone protecting step, a 21-acyloxy- 4,17()-pregnadiene-3,1l-dione (1), preferably 2l-acetoxy-4,l7(20)-[cis]-pregnadiene-3,1l-dione, is ketalized with an a-glycol or fl-glycol containing from one to eight carbon atoms, inclusive, e.g., ethylene glycol, propylene glycol, trimethylene glycol, octane-1,2-diol, to produce the 3-ketal thereof (II) wherein R is an alkylene dioxy group, or reacted with methyl alcohol, ethyl alcohol, benzyl alcohol, octyl alcohol, under the usual enol etherification conditions, to produce a 3-enol ether thereof (II) wherein R is a hydrocarbonoxy radical containing from one to twenty carbon atoms, inclusive, and a double bond is present in the 3(4)-position. I

The removal of the 21-ester group of the 3-ketone-protected 21-acyloxy-5,l7(20)-pregnadiene-3,l l-dione (II) preferably the 3-ethylene glycol ketal of 2l-acetoxy- 5,17(20)-[cis]-pregnadiene-3,1l-dione, involves a hydrolysis under the usual alkaline conditions. Although strong alkali, e.g., sodium hydroxide, can be employed, we have found that satisfactory results are obtained when employing an alkali-metal bicarbonate, preferably in an oxygen-free atmosphere. Hydrolysis of the 21-acyloxy group produces the corresponding 3-ketone protected 21- hydroxy-5,17(20)-pregnadiene-3,1l-dione (III) The ZI-etherification step involves the conversion of the 21-hydroxy group of a 3-ketone-protected 2l-hydroxy-5,l7(20)-pregnadiene-3,1l-dione (III), preferably 3-ethylene glycol ketal of 21-hydroxy-4,l7(20)-[cis]- pregnadiene-3,ll dione, to a 2l-hydrocarbonoxy group, i.e., etherification of the 21-hydroxy group to produce the corresponding 3-ketone protected 21-hydrocarbonoxy-S,17(20)-pregnadiene-3,1l-dione (IV). This can be accomplished by the usual etherification procedure, e.g., by reaction of a hydrocarbon halide or alcohol with III. The reaction is usually performed in the presence of an aromatic heterocyclic amine when a hydrocarbon halide is employed or in the presence of boron trifluoride orp-toluenesulfonic acid when anialcohol is. employed. An enol ether canv also be prepared by reaction of the 21-hydroxy group with areadily enolizable-ketone, e.g., dihydropyran, as disclosed in US. Patent 2,637,728. Examples of 21-ethers which can. be produced are the lower-alkyl ethers, e.g., methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, and aralkyl, e.g., benzyl, triphenylmethyl, etc.

An alternative route to a 3-ketalized-21-etherified 2l-hydroxy-5,17(20)-pregnadiene-3,1l-dione (IV) involves the reaction .of a 3-ketal of 115,21-dihydroxy- 5,17(20)-pregnadiene-3-one with an etherifying agent. as described above to produce a 3-rketal of llfl-hydroxy-Zlhydrocarbonoxy 5,17(20)pregnadiene 3 one and then oxidizing the 11,8-hydroxy group with chromic acid in acetic acid or N-bromoacetamide in pyridine, in the usual manner.

The alkylation step involves the reactionof a 3-ketoneprotected 2l-hydrocarbonoxy-5,17(20)-pregnadiene-3 ,11- dione (IV), preferably the 3-ethylene glycol ketal of .21- triphenylmethoxy-5,l7(20)-[cis]-pregnadiene 3,11-dione, with a lower-alkyl lithium, e.g., methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl or octyl lithium, preferably methyl lithium, to produce the corresponding 3-ketoneprotected 1 la lower-alkyl-l lB-hydroxy-2l-hydrocarbonoxy-5,l7(20)-pregnadiene 3 one (V). The lower-alkyl magnesium halides" ordinarily are not reactivetoward the ll-keto group whereas the lower-alkyl lithiums, and especially methyl lithium, react rapidly with ease with the ll-keto group. The usual reaction conditions for an alkylation with a lower-alkyl lithium are employed. Usually a reaction temperature of about room temperature, i.e., between twenty and thirty degrees centigrade, is employed for convenience and the good results obtained, although higher temperatures have been employed with success.

The hydrolysis step involves the removal of the 3- ketone protecting group and the 21-ether group of a 3-ketone-protected lla-lower-alkyl 115 hydroxy-Zl-hydrocarbonoxy-5,17(20)-pregnadiene-3-one (V), preferably the 3-ethylene glycol ketal of lla-methyl-llB-hydroxy-Zl-triphenylmethoxy'- 5,17(20) [cis]-pregnadiene- 3-one, to produce the corresponding lla-lower-alkyl- 1113,21 dihydroxy-4,17(20)-[cis]-pregnadiene-3-one (VI) according to methods known in the art, e.g., the starting ketone-protected steroid (V) is mixed with a hydrolyzing agent such as, for example,- dilute'aqueous hydrochloric acid, sulfuric acid, or other acidic 'hydrolyzing agent. Although both of these groups are ordinarily removed in the same reaction, their removal can be stepwise, with the 3-ketone-protecting group being removed first, if so desired. The 3-ketone protecting group is ordinarily more susceptible to hydrolysis than the 2l-ether group and is therefore more rapidly hydrolyzed to produce an lower alkyl 11/3 hydroxy 21 hydrocarbonoxy- 4,l7(20) pregnadiene 3 one. A 2l-tetrahydropyranyl ether, however, is hydrolyzed as rapidly or more so-than the corresponding 3-ketone-protecting group, thus producing B-ketalized a 1la-lower-alkyl-l1 8,21-dihydroxy- 5,17(20)-pregnadiene-3-one as the intermediate compound in the hydrolysis reaction.

Esterification of an lla-lower-alkyl-l1,8,21-dihydroxy- 4,l7(20)-pregnadiene-3-one (VI), preferably Ila-methyl- 11B,2l-dihydroxy-4,17(20)-[cis]-pregnadiene 3-one with an esterifying derivative of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms is productive of the corresponding 1lot-lower-alkyl-llfl-hydroxy-Zlacyloxy-4,17(20)-pregnadiene-3-one (VII). This reaction can be performed under the esterifications known in the art, e.g., by the reaction of VI with the selected acid anhydride or acid chloride or bromide of a hydrocarbon carboxylic acid, preferably in the presence of pyridine or like tertiary aromatic amine, or by reaction with the selected acid, in the presence of an esterification catalyst or with an ester under ester exchange conditions. Reaction conditions which are apt to affect the labile 11,3- hydroxy group should be avoided. Compounds thus produced include the compounds represented by Formula VII wherein the 17(20) configuration is cis, the ll-loweralkyl group is methyl and Ac is the 'acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric," trimethylacetic, Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, a-ethylisovaleric, a cyclic acid, e.g., cyclopropylideneacetic, cyclopentylformic, cyclopentylacetic, fi-cyclohexylpropionic, fi-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, an aryl or alkaryl acid, e.g., benzoic, 2-, 3-, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6 trimethylbenzoic, 2,4,6 triethylbenzoic, a-naphthoic, 3-methyl-wnaphthoic, an aralkyl, e.g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic, etc.

The oxidative hydroxylation reaction of the present invention converts a 1lot-lower-alkyl-l1B-hydroxy-21- acyloxy-4,17(20)-pregnadiene 3 one (VII), preferably lla-methyl-l 1,8 hydroxy 21 acetoxy 4,l7(20) [cis]- pregnadiene-3-one, to the corresponding Ila-loweralkyl-1l,B,17a-dihydroxy-2l acyloxy 4 pregnene 3,20- dione (VIII) by reaction with a catalytic amount of osmium tetroxide and an oxygen donating oxidizing tetroxide, calculatedonthe 'st'a'rting steriod,

"tiveof the products and process of the preset:

. ketal application of Lincoln and December 17,1954. x I v l 'A preferred procedure involves employing fr'om about two to about three molar' equivalents *of-the-'oxidizing Tgent and; les s'than'j0.05 molar equivalent 'o osmium tertiary butyl alcohol at about room teinperature-"'' W Substituting an 110; lower alkyl 115,21 dihydroxy- 4,17 (20)-pregnadiene-3-one for the corresponding 21- acyloxy compound as the starting steroid inlthe oxidative hydroxylation step is productive of the corresponding 11!: lower alkyl 11fl,17oi,2l trihydroxy 4 pregnene- .3,-20-dione. I 5

The following preparations andexarnple ,ar illustrainv n n but are notto be construed as limiting.

, PREPARATION i 1 J The 3-ethylene glycol ketal. of 21 -a,cetoxy,-5,1 7( 2 o)i,- i"cisl pregnadiene-3Jl-dione (ll) FA solution'of -0.50 gram (l.35 millirrioles) *of 121- acetoxyf4, 17 (20) -[cis] -,pregnadiene-3,1 1-dione, repared as disclosed in the copending, applicationof Hugger 51.,

S.N.1 345,675, ten milligrams of paratoluenesulfonic"acid and two milliliters of ethylene glycol in 100 millilitersbf benzene was refluxed forfsix hours with concomitant re- .moval of the water of reaction by passing there'turn' conf densate through a bed of calcium carbid'ef -*-The cooled solution was then washed withv an aqueous four percent.

solution of sodium bicarbonate, water and then dried. The dried solution was distilled at reduced pressure leavinga yellow oil which-sooncrystallized.-- Thecrystals were recrystallized from a mixture of ethyl acetatefand Skellysolve B (hexane hydrocarbons) to give0.27

of the 3-ethylene glycol ketal of 2l-acetoxy-5,17 (20)- [cis]-pregnadiene-3,1l-dione melting at 160 to 162 degrees 'centigrade and having the analysis below."

Calculated for C H O C, 72.43;H, 8.27. ,FOund: C, 72.11;H, 8.44.

. l PREPARATIQN 2,;. x The S-ethylene gly'cdl ketal of 2'1-hydr0xy-5,'17-(20)'-'-[sis]- pregnadiene-3,11-dione (II!) To a solution of ten grams (0.024 mole) of the 3-ethylene glycol ketal of 21-acetoxy-5,l7(20)-[cisl-pregnadiene-3,11-dione in 1,500 milliliters of absolute methanol, in a nitrogen atmosphere, was added a solution of ten grams (0.1 mole) of potassium bicarbonate in 100 milliliters of water at a temperature of about 25 degrees centigrade. The mixture was stirred for one hour and then maintained at room temperature for eighteen hours, in a nitrogen atmosphere. The mixture was distilled to a small volume at reduced pressure and then diluted with stirring with 500 milliliters of water. Crystals precipitated from the mixture which were filtered, washed with water, anddriedto give 8.46. grams. 0154 16 3,- hyene 8 119 of g 2 l-hydroxy-S 17 20 [cis -pregnadiene-3 ,1 1- dion e melting at l09 to 111.5 degrees centigrad. Recrystallization of this product from fifty percent aqueous methanol gave crystals meltingYat 11315 to 115 degrees centigrade and havingithe analysis below.

1 Calculated for C H O C, 74.l6; H, 8.66. Found:

l t PREPARATION3 g x The 3 ethyleneglyco1"ketal of 21-triph'enylmeth0xy- 5 ,1 7(20) [cis] -pregnadiene-3,1 I -dione: l V):

ene glycol ketal of 21-hydroxy-5,17(20) ieisl pregnaanalysis below.

.-,with.water and then dried with anhydrous POtassiurncarbonate. The dried solution distilled to dryness 10 }leaving a glass which was crystallized from m mento .give 6.19 grams of the 3-ethylene glycohketalbf 2 tri ,dione melting at 195 to '198"degreesfcentig r e.

..1tallization-from a mixtureofether and ,methanol arsed t e melting point to .201 to [203 d greesfcen rade. flhese crystals had the analysis below. I Calculated for C l-1 0 C, 82.05; H, 7.54. und:

. EXAMPLE 11. a

The 3-ethylene glycolketal of lla-methyldlfl-hydroxy- 21 triphenylmethoxy 5,17(20) [-cis] pregna'dienc- 3-one (V) Y To a solution of 300 miligrams of the3-ethylene glycol ketal of 21-triphenylmethoxy-5,l7(20 [cisl-pregnadiene- 3,11-dione in five milliliters of anhydrous benzene in a dry atmosphere of nitrogen was added ten milliliters of; a 0.33 molar solution of methyl lithium in anhydrous ether. The sealed container containing the solution was maintained for three days at about 25 degrees centigrade. The solution was diluted with benzene andthen washed with six milliliters of a 1:5 solution of acetic acid in water and then with several portions of water. The benzene solution was dried and then distilled to dryness. 'The residue was chromatographed over a thirty gram column of Florisil (synthetic magnesium silicate).' The column was developed with sixty-milliliter portions of Skellysolve B (hexane hydrocarbons) containing increasing proportionsof acetone. A 294 milligram yieldiof-"the 3-ethylene glycol ketal of 1la-methyl-lIB-hydroxy-Zl-triphenylmethoxy-S, 17( 20) [cis -pregnadiene-3-one was eluted from the column with Skellysolve B plu'sfi've percent acetone. The thus-purified material wasrecrystallizedfroin a mixture'of ethyl acetate and methanol to'give product melting at 182 to 184 degrees centigrade and having the Calculated for 0 11 0,: 0, 81.87; H, 7.93." Found:

' A suspension of 200 milligrams (0.32millimole) :o f the '3-ethylene glycol ketal of lla-methyl l lfl-hydroxy-2 ltriphenylmethoxy-S,17(20) pregnadiene-3 one in twenty milliters of methanol containing one milliliter of 1'-N h ydrochlori'c acid was stirred at room temperature for two days, during which time the suspended solid gradually dissolved. The solution was mixed with fifteen milliliters thirty milliliters of benzene.

of 1.3 percent aqueous sodium bicarbonate and then evaporated to dryness. The residue was triturated with The benzene solution was poured over a thirty gram column of Florisil ,(synthetic magnesium silicate). The column was developed with sixty milliliter portions of solvent of the following composition and order: six of Skellysolve B(hexanehydrocarbons), six of Skellysolve B plus five percent acetone, six of Skellysolve B plus ten percent acetone, six of Skellysolve B plus 25 percent acetone and six of acetone. The middle four Skellysolve B plus 25 percent acetone eluate fractions contained 78 milligrams of Ila-methyl- 11;8,21 dihydroxy 4,17(20) [cis] pregnadiene 3 onewh ich, when recrystallized from ethyl acetate, melted at 188 to 192 degrees centigrade and had the analysis below. 7 I $.11

Calculated for C H O C, 76.70; H, 9.36. Found: C, 76.31; H, 9.50.

EXAMPLE 3 A solution of about 2000 milligrams of 11,8,21-dihydroxy-l1a-methyl-4,17(20) [cis] -pregnadiene'3-one in 25 milliliters of pyridine was mixed with 25 milliliters of acetic anhydride and the Whole was then maintained at room temperature for three days whereafter the mixture was poured over crushed ice. The precipitated oily llfl-hydroxy-lla-methyl 21 acetoxy 4,17(20)-[cis]- pregnadiene-3-one was recovered by extraction with methylene chloride and then chromatographed over a column of fifty grams of Florisil (synthetic magnesium silicate). The column was developed with 350-milliliter portions of Skellysolve B (hexane hydrocarbons) containing increasing percentages of acetone. The eluate fractions containing seven percent acetone eluted 1.994 grams of 113 hydroxy 11cc methyl 21 acetoxy- 4,17(20)-[cisJ-pregnadiene-3-one which, when crystallized from a mixture of ethyl acetate and Skellysolve B, melted at 107-113 degrees centigrade.

Similarly, other 21-organic carboxylic acid esters of 115,21 dihydroxy 11a methyl 4,17(20) [cis]- pregnadiene-3-one are prepared wherein the 21-acyloxy group is formyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoyloxy, phenylacetoxy, or the like, by contacting 1113,21-dihydroxy-lla-methyl 4,17(20) pregnadiene 3 one with an appropriate acylating agent, e.g., the anhydride or acid halide of the selected acid in a solvent such as, for example, benzene, toluene, acetic acid, or the like.

EXAMPLE 4 lla-methyl-l 1 3,1 7a-dihydroxy-21-acet0xy-4-pregnene- 3,20-dine (VIII) To a solution of 681 milligrams of 1lu-methyl-1113- hydroxy-21-acetoxy-4,17(20) [cis] pregnadiene-3-one dissolved in 33.5 milliliters of tertiary butyl alcohol was added 0.4 milliliter of pyridine followed by a solution of 730 milligrams of N-methylmorpholine oxide peroxide in 3.47 milliliters of tertiary butyl alcohol and 0.56 milligram of osmium tetroxide in 1.02 milliliters of tertiary butyl alcohol. The N-methylmorpholine oxide peroxide was prepared by the reaction of N-methylmorpholine with two molar equivalents of hydrogen peroxide in tertiary butyl alcohol. The mixture was maintained at about 25 degrees centigrade for twentyfive hours and then mixed with 370' milligrams of Magnesol filter aid and 9.2 milliliters of aqueous 0.5 percent sodium hydrosulfite solution. After one-half hour the mixture was filtered and most of the tertiary butyl alcohol distilled from the filtrate at reduced pressure and at a temperature less than sixty degrees centigrade. The concentrate was diluted with about 35 milliliters of water and extracted with four 25-milliliter portions of methylene chloride. The combined extracts were washed with sixty milliliters of water, filtered through anhydrous sodium sulfate and concentrated to dryness at reduced pressure. The resultant oil was redissolved in methylene chloride and chromatographed over a column of fifty grams of acid-washed alumina, the height: diameter ratio of the column being about 4:1. Elution was carried out by a solvent gradient technique. The initial eluting solvent was methylene chloride. The initial volume of solvent in the reservoir above the column was 1,000 milliliters. This volume was maintained constant by the gradual addition of 800 milliliters of methylene chloride plus twenty percent acetone. When this solvent had all been added to the reservoir, 800 mililiters of in the reservoir discarded and the columnwas stripped with methanol. The desired product was obtained by evaporation of the 1,150 milliliters of eluates which immediately preceded the methanol eluates. The 268 milligrams of crude product thus-obtained was crystallized from ethyl acetate to give 11a-methy1-11fi,17a-dihydroxy-Z1-acetoxy-4-pregnene-3,20-dione melting at 192 to 197 degrees centigrade.

EXAMPLE 5 1 1 a-methyl-I 118,1 711,2] -trihydr0xy-4 pregnene-3,20-

dione VIII) A solution of 418 milligrams of 11a-methyl-hydrocortisone acetate in four milliliters of methanol Was freed of oxygen gas by bubbling nitrogen therethrough. A solution of 404 milligrams of potassium bicarbonate in four milliliters of water was similarly freed of oxygen. The two solutions were mixed at a temperature of between eighteen and' twenty degrees centigrade and in a nitrogen atmosphere. The temperature of the solution rose to between 24 and 26 degrees centigrade. The mixture was stirred at room temperature for five hours while protecting it from atmospheric oxygen with nitrogen. At the end of five hours the solution was neutralized with very dilute acetic acid. The neutralized solution was concentrated by distillation at room temperature and then chilled in a refrigerator for about sixteen hours. The, thus-precipitated lla-methyl-hydrocortisone was filtered, washed with ice water and then dried.

1la-methyl-hydrocortisone can also be prepared by substituting Ila-methyl 11,6,21 dihydroxy 4,17(20)- [cis]-pregnadiene-B-one as the starting steroid in Example 4.

It is to be understood that the invention is not to be limited to the exact details of operation described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. 3-cyclic ketal-21-hydrocarbon ethers of Ila-loweralkyl-11B,21 dihydroxy 5,17(20) pregnadiene 3-one represented by the following formula:

('3Hr-O-hydrocarbon CH lower-alkyl l OH; CH---O wherein R is selected from the group consisting of hydrogen and lower-alkyl, n is a whole number from one to two, and the 21-hydrocarbonoxy radical containsfrom one to twenty carbon atoms, inclusive.

2. The 3-ethylene glycol ketal of 11a-methyl-11fi-hydroxy-21-triphenylmethoxy 5,17(20)-[cis]-pregnadiene- 3-one.

3. The process whichcomprises alkylating a compound selected from the group consisting of 3-cyclic ketals and 3-enol ethers of 21-hydrocarbonoxy-S,17(20)- pregnadiene-3,11-dione with a lower-alkyl lithium compound to produce the corresponding lla-lower-alkyl-l 1phydroxy compound.

1% 4. The process of claim 3 wherein the 1ower-a1kyl References Cited in the file of this patent lithium compound is methyl lithium. UNITED STATES PATENTS 5. The process of claim 3 wherein the lower-alkyl lithium is methyl lithium and the starting steroid is the 2'707184 Hogg et a1 1955 3-ethylene glycol ketal of 21-triphenylmethoxy-5,17(20) 5 2,713,061 Kathol July 1955 [cisLpregnadieneflJ1-di ne 2,713,062 Junkmann y 1955 

1. 3-CYCLIC KETAL-21-HYDROCARBON ETHERS OF 11A-LOWERALKYL-11B,21 - DIHYDROXY - 5,17(20) - PREGNADIENE - 3-ONE REPRESENTED BY THE FOLLOWING FORMULA: 